Abstract

OBJECTIVE— The utility of rapid and reliable sensory tests
appropriate for the diagnosis of neuropathy in the diabetes clinic, rather
than as prognostic tools for the prediction of foot complications, has been
unclear because of limitations inherent in previous studies. Although clinical
practice guidelines recommend annual screening for neuropathy, they are unable
to support specific recommendations for screening maneuvers because of a lack
of evidence for the validity of screening tests in the medical literature. The
objective of this study was to assess the operating characteristics of four
simple sensory screening maneuvers as compared with standardized
electrophysiological tests in the diagnosis of distal symmetrical
polyneuropathy.

RESEARCH DESIGN AND METHODS— We assessed four simple tests
(the 10-g Semmes-Weinstein monofilament examination [SWME], superficial pain
sensation, vibration testing by the on-off method, and vibration testing by
the timed method) in 478 subjects with independent blinded evaluations
compared against the criterion standard of nerve conduction studies. We
present receiver-operating characteristic (ROC) curves, positive and negative
likelihood ratios, and sensitivity and specificity values for each test.

RESULTS— The four simple screening maneuvers reveal similar
operating characteristics. Cutoff points by ROC curve analyses reveal that a
positive or abnormal test is represented by five incorrect responses of eight
stimuli applied. A negative or normal test is represented by one or fewer
incorrect responses of eight stimuli applied. By these criteria, the point
estimates of the positive likelihood ratios for vibration testing by the
on-off method, vibration testing by the timed method, the SWME, and
superficial pain sensation test are 26.6, 18.5, 10.2, and 9.2, respectively.
The point estimates of the negative likelihood ratios are 0.33, 0.51, 0.34,
and 0.50, respectively. The screening tests showed comparable sensitivity and
specificity results. The 10-g SWME, superficial pain test, and vibration
testing by the on-off method are rapid, each requiring ∼60 s to
administer. The timed vibration test takes longer, and the interpretation is
more complicated. The combination of two simple tests (e.g., the 10-g SWME and
vibration testing by the on-off method) does not add value to each individual
screening test.

CONCLUSIONS— Annual screening for diabetic neuropathy should
be conducted using superficial pain sensation testing, SWME, or vibration
testing by the on-off method. The reported operating characteristics for each
sensory modality can be applied to positive findings on the physical
examination of individual patients to predict the likelihood of
neuropathy.

The chronic peripheral neuropathy associated with diabetes represents an
insidious and progressive process, the pathological severity of which is
poorly linked with the development of symptoms
(1,2).
It is the component cause that initiates the pathophysiological pathway to leg
ulceration and amputation, and by itself it is sufficient cause for painful
paresthesia, sensory ataxia, and Charcot deformity
(3). Screening and the early
identification of the neuropathic process offer a crucial opportunity for the
patient with diabetes to actively alter the course of suboptimal glycemic
control and to implement improved foot care before the onset of significant
morbidity. The Diabetes Control and Complications Trial
(4) demonstrated that intensive
insulin therapy in type 1 diabetes reduced the risk of developing clinical and
electrophysiological deficits of diabetic neuropathy by 61%; similarly, the
U.K. Prospective Diabetes Study reported a relative risk of 0.60 (95% CI
0.39-0.94, P=0.0052) for neuropathy as measured by a biothesiometer
for a mean of 15 years of follow-up in the intensive policy group
(5). Furthermore, independent
electrophysiological studies have demonstrated the relationship between
glycated hemoglobin and the presence and severity of neuropathy
(6). In addition, potential new
therapies, such as aldose reductase inhibitors and protein kinase C
inhibitors, stress the importance of early intervention facilitated through a
valid screening mechanism in the diabetes clinic
(7,8,9,10,11).

Clinical trial evidence for the efficacy of screening strategies
demonstrated reduced outcomes of amputation and ulceration
(7,8,12,13,14,15,16),
and, consequently, screening for neuropathy is recommended in clinical
practice guidelines
(17,18).
The current level of evidence for the optimal screening method, however, is
limited by study cohorts with a restricted spectrum of disease, the lack of
independently blinded examiners for individual screening tests, and the
inconsistent use of an objective criterion standard. In addition, inconsistent
reporting of the required statistical operating characteristics limit the
clinical applicability of the results. Nerve conduction studies (NCSs) are
strongly correlated with underlying structural changes and are the least
subjective and most reliable single criterion standard
(19,20,21,22,23,24).

This study evaluates four standard simple screening maneuvers appropriate
for the diabetes clinic (i.e., 10-g Semmes-Weinstein monofilament examination
[SWME], superficial pain, vibration testing by the on-off method, and
vibration testing by the timed method) for the detection of neuropathy using
NCSs as the criterion standard in a large mixed population of nondiabetic
reference subjects and diabetic patients with a spectrum of neuropathy.

RESEARCH DESIGN AND METHODS

The study was conducted at the
Toronto General Hospital/University Health Network (UHN) in the Diabetic
Neuropathy Research Clinic from June 1998 to August 1999. Approval from the
UHN Research Ethics Board was obtained before commencing the study. Informed
consent for the study was obtained from each subject by an unblinded
observer.

Selection of patients

The inception cohort was ascertained from four different sources:
unselected patients attending a diabetes clinic with unknown neuropathy
status, patients referred to the Diabetic Neuropathy Research Clinic for
suspected neuropathy, people with unknown neuropathy status who were recruited
through advertisements in the community for patients with diabetes, and
reference subjects.

Study protocol

All subjects underwent the following procedures: 1) a
comprehensive medical and neurological evaluation to exclude neuropathy of
other etiologies (e.g., familial, alcoholic, nutritional, and uremic)
performed by the unblinded observer who had obtained the informed consent;
2) standardized bilateral NCSs—including motor (peroneal,
tibial, median, and ulnar) and sensory (sural, median, and ulnar)
nerves—performed by technicians who were blinded to the status of the
subject; 3) a 10-g SWME performed by an independent observer who was
blinded to all other results, including history and physical examination; and
4) a vibration sense (by the on-off and timed methods) and
superficial pain sensation test performed by three different independent
observers per patient blinded to all other results, including history and
physical examination.

Each subject was assessed by at least seven different examiners during a 4-
to 5-h stay in the clinic. Triplicate screening tests were performed in a
subset of subjects using nine different examiners. All data were entered on
standardized forms identifying subjects only by number, date of birth, and
initials. Data entry was performed by a clerk without knowledge of the
category of the subject. Prior to commencing the trial, training and practice
sessions were held for all examiners to standardize the testing methods for
each screening test.

Clinical stratification method

A clinical stratification method was used to ensure a broad spectrum of
patients in the study. The decision was made to close recruitment when the
smallest stratum contained 50 subjects. Subjects were graded according to
neuropathy severity using 6 symptom scores (the presence or absence of foot
pain, numbness, tingling, weakness, imbalance, and upper limb symptoms), 8
reflex scores (bilateral knee and ankle reflexes, each graded as absent,
reduced, or normal), and 5 physical examination scores (the presence or
absence of pinprick, temperature, light touch, vibration, and position sense)
for a total of 19 possible points. Grading was stratified such that ≤5
indicated no neuropathy, 6-8 indicated mild neuropathy, 9-11 indicated
moderate neuropathy, and ≥12 indicated severe neuropathy.

Sensory testing methods

For each testing modality, the patient was given a reference sensation by
application of the stimulus to the sternum and then asked the nature of the
sensation perceived. When the nature of the sensation was perceived accurately
on the sternum, the subject was asked, with eyes closed, to describe the
sensations experienced sequentially at the sites described below.

The SWME was conducted using a 5.07/10-g monofilament applied to a
noncallused site on the dorsum of the first toe just proximal to the nail bed.
It was repeated four times on both feet in an arrhythmic manner by an
independent examiner, who circled correct responses on the scoring sheet and
then added the number of errors. The SWME threshold was defined as the total
number of times the application of the 10-g monofilament was not perceived by
the subject, and it varied from 0 to 8.

Vibration testing by the on-off method was conducted using a 128-Hz tuning
fork applied to the bony prominence bilaterally situated at the dorsum of the
first toe just proximal to the nail bed. The patient was asked to report the
perception of both the start of the vibration sensation and the cessation of
vibration on dampening. The testing was conducted twice on each toe, and
correct responses were circled on a standardized sheet. The vibration testing
threshold was defined as the total number of times the application of the
vibrating tuning fork and the dampening of vibration was not felt, with scores
varying between 0 and 8.

Vibration testing by the timed method was conducted using a 128-Hz tuning
fork applied to the same bony prominences bilaterally situated at the dorsum
of the first toe. The patient was asked to report the time at which vibration
diminished beyond perception. The tuning fork was then applied to the dorsal
aspect of the distal phalanx of the examiner's thumb. The time (in seconds) at
which vibration sensation diminished beyond the examiner's perception was then
recorded on a standardized form. The values from both sides were added to
provide a single score for statistical analyses.

Superficial pain sensation was conducted using a sterile Neurotip (Owen
Mumford, Oxford, U.K.) applied four times in an arrhythmic manner to the two
sites described for the SWME. The superficial pain threshold was defined as
the total number of times the application of the pain sensation was not
perceived, with scores varying from 0 to 8.

Measurements of each sensory modality and the NCSs were performed by
separate observers blinded to the subject's history and physical examination
and to the results of the other tests. The physician performing the complete
history and physical examination was unaware of the results of the individual
sensory parameters tested and the NCSs.

The interobserver variability for each sensory modality was assessed by
triplicate independent blinded testing in a subset of at least 10 subjects
assessed by three different examiners.

Criterion standard

Standardized techniques for NCSs were applied with temperature control and
fixed distances. Measurements of latencies, distances, and amplitudes were
assessed in a standard fashion using onset latencies and baseline-to-peak
amplitudes. Initial positive peak (if present)-to-negative peak measurements
were conducted for sensory responses. F waves were generated for all
motor nerves, and minimal, reproducible latencies were measured. Conduction
velocities were calculated for motor and sensory nerves.

All conduction velocity and distal amplitude values for the NCSs were given
a score of 0 for normal and 1 for abnormal. The mean reference values ±
2 SD were taken as the normal range. The maximum NCS score if all parameters
were abnormal was 28 points (16 motor and 12 sensory). The total NCS score was
defined as the sum of the number of abnormal values.

Statistical analyses

The χ2 test was used to detect differences of clinical
characteristics across the five strata. P ≤ 0.01 was considered
statistically significant.

Based on the binomial distribution, the sign test justifies the use of
eight responses for each sensory modality score
(25). On stimulation with a
testing modality, the probability of seven of seven random correct responses
by chance alone is 0.0078, which is acceptable using the customary cutoff
chosen as a criterion for statistical significance.

Receiver-operating characteristic (ROC) curves were generated for each
sensory modality, and area under the curve (AUC) and optimal cutoff points
were determined.

Comparison of the different screening methods was assessed using Spearman's
rank-correlation coefficient and Pearson's correlation coefficient when
applicable. Logistic regression modeling was conducted to confirm the AUC
measurements for the cutoff points of each sensory modality test as single
predictors of NCS scores. The modeling was repeated by controlling for
neuropathy strata, which afforded the opportunity to assess 1)
whether a sensory modality test was a reliable predictor of NCS scores and
2) whether the observed association was real or spurious. Positive
and negative likelihood ratios were evaluated and interpreted in terms of the
odds of having an abnormal test result in a neuropathy group (i.e., patients
having abnormal NCS scores) compared with a nonneuropathy group (i.e.,
patients having normal NCS scores). For the subset of subjects who had
triplicate screening tests, Wilcoxon's rank-sum test (using the Kruskal-Wallis
test) was used for the reproducibility of the screening tests.

RESULTS

The demographic profile of the study population is
shown in Table 1. Significant
differences were observed between the defined clinical strata as follows: age
of patients (with the reference group being younger), duration of diabetes
(longer for more severe neuropathy, P < 0.0001), and duration of
neuropathy (longer for more severe neuropathy, P < 0.0001).
Contingency table analyses revealed a significantly increasing prevalence of
history of foot ulcer, retinopathy, nephropathy, and erectile dysfunction with
stage of neuropathy. The χ2 and P values are shown in
Table 2.

—ROC curves for each simple test compared with NCS (gold
standard) plotting the sensitivity versus 1-specificity (the false-positive
rate) for different test cutoff points. The AUC values are for the cutoff
points listed in Table 3 (values
derived from multiple linear regression modeling).

Logistic regression modeling determined the optimal cutoff points for the
sensitivity and specificity values and, thus, the positive and negative
likelihood ratios as shown in Table
3. Of the four sensory modalities, vibration testing by the on-off
method had the highest positive likelihood ratio and a low negative likelihood
ratio. The specificity was 99% for five or more insensate responses.
Sensitivity was 56% for two or more insensate responses, and specificity
remained high at 92% for this test. Both the 10-g monofilament and superficial
pain modalities had comparable likelihood ratios (10.2 and 9.2), but better
sensitivity was observed with the 10-g monofilament (40%) and better
specificity was observed for superficial pain (97%). Vibration testing by the
timed method had comparable results. For this method, the value of 20 was
derived from a maximum of 10 s per toe for the lower cutoff for the necessary
likelihood ratios, and 40 was derived from a maximum of 20 s per toe for the
upper cutoff. Thus, the limits per toe were 10 and 20 s, respectively.

The operating characteristics of a score derived from the combination of
vibration testing by the on-off method and SWME testing did not differ
significantly from those of each individual modality. For the same cutoff
point of ≥10, the specificity was 98% and the positive likelihood ratio was
14.1. For the cutoff point of ≤2 for both, the sensitivity was 80% and the
negative likelihood ratio was 0.28.

For the subset of patients with repeated testing of each screening
modality, Table 4 shows the
P values of the Kruskal-Wallis χ2 test approximation
for reproducibility. The lack of a significant difference in P values
suggests that each screening test can be reproduced without any significant
bias attributable to the different examiners performing the test.

Table 5 shows the prevalence
of abnormal test results in each clinical stratum. The percentage of abnormal
test results increased with increasing severity of clinical diabetic
polyneuropathy (DPN), and the SWME best approached the levels of abnormality
observed for NCSs.

SWMEs, superficial pain sensation testing, and vibration testing by the
on-off method each required <60 s to perform accurately. Vibration testing
by the timed method took longer depending on the degree of normalcy.

CONCLUSIONS

The neuropathies associated with diabetes
represent insidious and progressive processes for which the pathological
severities are poorly linked with the development of symptoms. DPN is a
specific form of axonal neuropathy associated with diabetes and is defined
clinically by progressive disease that first includes distal and symmetrical
peripheral neuropathy of sensory nerve fibers, with eventual autonomic and
motor involvement
(3,26).

Polyneuropathy is a diabetes complication that is prevalent, responsible
for more than half of all limb amputations, and known to have well-defined
economic and quality-of-life costs
(27). Moreover, a long
asymptomatic latency period is understood as part of the natural history.
Allocation of appropriate interventions in high-risk patients with diabetes
has been shown to decrease the rate of ulceration by up to 60% and the rate of
amputation by 85% (13). The
main point of contention regarding screening for DPN is the efficacy of
treatment. Currently, no specific pharmacological agent has demonstrated
efficacy in reversing neuropathy or preventing disease progression beyond the
intervention of optimizing glycemic control
(4,28,29).
Clearly, autonomic dysfunction and somatic neuropathy symptoms and signs are
diminished with intensified glycemic control
(4). However, it is crucial to
remember that communicating information regarding the status of a patient's
diabetes complications may provide the impetus and empowerment for active
participation in the management of the patient's own disease. Screening for
neuropathy in the diabetes clinic is therefore justified for diagnosis,
patient education, the provision of further impetus for optimization of
glycemic control, and the institution of improved foot care for the reduction
of lower-extremity complications
(4,13).

The optimal method for the detection of neuropathy in patients with
diabetes has also been a matter of controversy, and clinical practice
guidelines have been based primarily on expert opinion rather than clinical
trial evidence
(17,18).
Clinical practice guidelines either do not recommend a specific screening
modality (18) or make
recommendations based on grade D evidence
(17). The Rochester Neuropathy
Score method (30) and the
Michigan Neuropathy Screening Instrument
(31) are accurate and
comprehensive strategies, though time-consuming and costly. These strategies
are more suitable for a specialized neurology clinic or research protocol than
for general screening in a diabetes or primary care clinic. As a result, these
methods are not in routine use by physicians caring for patients with
diabetes.

The current level of evidence in the medical literature for the use of
simple screening methods for DPN focuses primarily on the use of the
Semmes-Weinstein 5.07/10-g monofilament. The SWME allows for a simple
calibrated means of assessing protective sensation
(32,33)
and has been established as a prognostic risk factor for complications of
neuropathy. The monofilament is clearly established as a reproducible and
practical method (33). A
single prospective study investigating the operating characteristics of the
monofilament for the prediction of ulcers and amputations reports a positive
likelihood ratio of 15 (12).
Several case-control studies report variable sensitivities and specificities
up to 95 and 82%, respectively
(14,15,34,35).
The utility of the SWME as a screening method for the diagnosis of
neuropathy—rather than a prognostic tool for the prediction of foot
complications—has been unclear before the results of the current study
because of limitations inherent in previous trials. The current level of
evidence is limited by the restricted spectrum of neuropathy in the study
cohorts and the lack of independently blinded examiners for individual
screening maneuvers. The lack of a clearly defined and reliable criterion
standard
(16,36)
and inconsistent reporting of the required statistical operating
characteristics are features of the current literature. Negative likelihood
ratios for the finding of a normal screening test have not been defined
previously
(14,32,33,36).

The results of this study demonstrate for the first time reliable operating
characteristics of simple neurological examination maneuvers using a
methodologically sound trial design. The study subjects represented a broad
spectrum of neuropathy in terms of extent of disease. The inception cohort
consisted of a range of patients offering a diagnostic challenge and did not
simply represent groups that were stratified into case and control groups
consisting of subjects at either end of the spectrum of disease severity. The
testing methods were detailed and reproducible, and the methodology prohibited
the screening test results from influencing either the decision to perform
NCSs or the interpretation of NCS results.

The 10-g SWME, vibration testing with a 128-Hz tuning fork, and superficial
pain sensation testing individually generated positive likelihood ratios with
large and conclusive changes from pretest to post-test probability for DPN.
Negative likelihood ratios in the presence of normal testing generated small
but important changes in probability. The results of this study are simple to
interpret: for the SWME, superficial pain sensation test, and vibration test
by the on-off method, if more than one-half of the responses are incorrect (at
least five incorrect responses of eight stimuli), then peripheral neuropathy
is ruled in. One or fewer incorrect responses rule out peripheral neuropathy
by these methods. For vibration testing by the timed method, testing is more
time-consuming, and the results are less valid in their interpretation.
Vibration tested by the different methods provided different sensitivity and
specificity values, probably due to the different testing paradigms. This
finding indicates the absolute necessity of following described procedures in
the application of any testing method if one is using the results presented in
the literature. The combination of two testing modalities does not improve the
operating characteristics of screening from the data in this study.

We found that any one of these three simple tests (10-g SWME, superficial
pain, and vibration testing by the on-off method) can be confidently used for
annual screening of diabetic neuropathy in both diabetes and primary care
clinics.

Diabetes Control and Complications Trial Research Group: The effect
of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med329:977
-986, 1993